Kieren A. Marr, MD; Haran T. Schlamm, MD; Raoul Herbrecht, MD; Scott T. Rottinghaus, MD; Eric J. Bow, MD, MSc; Oliver A. Cornely, MD; Werner J. Heinz, MD; Shyla Jagannatha, PhD; Liang Piu Koh, MBBS; Dimitrios P. Kontoyiannis, MD; Dong-Gun Lee, MD; Marcio Nucci, MD; Peter G. Pappas, MD; Monica A. Slavin, MD; Flavio Queiroz-Telles, MD, PhD; Dominik Selleslag, MD; Thomas J. Walsh, MD; John R. Wingard, MD; Johan A. Maertens, MD, PhD
Acknowledgment: The authors thank the patients, coordinators, and nurses involved in the study, and members of the Mycoses Study Group for advice in the design, administrative coordination, and implementation of the DRC. Editorial support was provided by Complete Medical Communications and was funded by Pfizer. The authors thank the site investigators who are listed in Supplement 3.
Grant Support: By the National Institute of Allergy and Infectious Diseases (K24 AI085118; Dr. Marr).
Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-2508.
Reproducible Research Statement:Study protocol: Sections available at www.clinicaltrials.gov/ct2/show/NCT00531479. Statistical code and data set: Applications for access can be made to Pfizer via www.pfizer.com/research/clinical_trials/trial_data_and_results/data_requests.
Requests for Single Reprints: Kieren A. Marr, MD, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 1064, Baltimore, MD 21205; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Marr: Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 1064, Baltimore, MD 21205.
Dr. Rottinghaus: Pfizer, 235 East 42nd Street, New York, NY 10017.
Dr. Schlamm: Cidara Therapeutics, 6310 Nancy Ridge Drive, Suite 101, San Diego, CA 92121.
Dr. Herbrecht: Centre Hospitalier Universitaire de Strasbourg, Hôpital de Hautepierre, 1 Avenue Molière, Strasbourg Cedex, France 67098.
Dr. Jagannatha: Johnson & Johnson, 1125 Trenton-Harbourton Road, Titusville, NJ 08560.
Dr. Bow: University of Manitoba, Faculty of Health Sciences, College of Medicine, c/o Infection Control Services, CancerCare Manitoba, 675 McDermot Avenue, Winnipeg, Manitoba R3E 0V9, Canada.
Dr. Cornely: University Hospital of Cologne, Kerpener Street 62, Cologne 50937, Germany.
Dr. Heinz: University of Würzburg Medical Centre, Sanderring 2, Würzburg 97080, Germany.
Mr. Koh: National University Cancer Institute, National University Health System, 5 Lower Kent Ridge Road, 119074 Singapore.
Dr. Kontoyiannis: University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030.
Dr. Lee: College of Medicine, The Catholic University of Korea, Seoul St. Mary's Hospital, 222 Banpo-daero, Seocho-gu, Seoul, South Korea 137-701.
Dr. Nucci: Hospital Universitario, Universidade Federal do Rio de Janeiro, Rua Prof. Rodolpho Paulo Rocco 255, Rio de Janeiro, Brazil 21941-913.
Dr. Pappas: University of Alabama at Birmingham Medical Center, 500 22nd Street South, Birmingham, AL 35233.
Dr. Slavin: Peter MacCallum Cancer Centre, St. Andrews Place East Melbourne, Victoria 3002, Australia.
Dr. Queiroz-Telles: Hospital de Clínicas, Universidade Federal do Paraná, Rua XV de Novembro, 1299-Centro, Curitiba, Paraná 80060-000, Brazil.
Dr. Selleslag: Algemeen Ziekenhuis Sint-Jan, Ruddershove 10, 8000 Brugge, Belgium.
Dr. Walsh: Weill Cornell Medical Center, Cornell University, 1300 York Avenue, New York, NY 10065.
Dr. Wingard: University of Florida, 1600 Southwest Archer Road, Gainesville, FL 32610.
Dr. Maertens: Universitaire Ziekenhuizen Leuven, Campus Gasthuisberg, Brusselsestraat 69, 3000 Leuven 3000, Belgium.
Author Contributions: Conception and design: K.A. Marr, H.T. Schlamm, R. Herbrecht, S.T. Rottinghaus, E.J. Bow, O.A. Cornely, M. Nucci, M.A. Slavin, J.R. Wingard, J.A. Maertens.
Analysis and interpretation of data: K.A. Marr, H.T. Schlamm, S.T. Rottinghaus, E.J. Bow, O.A. Cornely, W.J. Heinz, S. Jagannatha, L.P. Koh, P.G. Pappas, M.A. Slavin, D. Selleslag, T.J. Walsh, J.R. Wingard.
Drafting of the article: K.A. Marr, H.T. Schlamm, S.T. Rottinghaus, E.J. Bow, O.A. Cornely, W.J. Heinz, D.G. Lee, M.A. Slavin, F. Queiroz-Telles, T.J. Walsh, J.A. Maertens.
Critical revision of the article for important intellectual content: K.A. Marr, H.T. Schlamm, R. Herbrecht, S.T. Rottinghaus, E.J. Bow, O.A. Cornely, W.J. Heinz, D.P. Kontoyiannis, D.G. Lee, M. Nucci, P.G. Pappas, M.A. Slavin, D. Selleslag, T.J. Walsh, J.R. Wingard, J.A. Maertens.
Final approval of the article: K.A. Marr, H.T. Schlamm, R. Herbrecht, S.T. Rottinghaus, E.J. Bow, O.A. Cornely, W.J. Heinz, L.P. Koh, D.P. Kontoyiannis, D.G. Lee, M. Nucci, P.G. Pappas, M.A. Slavin, F. Queiroz-Telles, D. Selleslag, T.J. Walsh, J.R. Wingard, J.A. Maertens.
Provision of study materials or patients: R. Herbrecht, E.J. Bow, O.A. Cornely, W.J. Heinz, L.P. Koh, D.P. Kontoyiannis, M. Nucci, P.G. Pappas, D. Selleslag, J.A. Maertens.
Statistical expertise: E.J. Bow, S. Jagannatha.
Obtaining of funding: P.G. Pappas.
Administrative, technical, or logistic support: S.T. Rottinghaus, E.J. Bow, P.G. Pappas.
Collection and assembly of data: K.A. Marr, H.T. Schlamm, S.T. Rottinghaus, E.J. Bow, O.A. Cornely, S. Jagannatha, L.P.K., D.P. Kontoyiannis, M.A. Slavin, F. Queiroz-Telles, T.J. Walsh, J.R. Wingard, J.A. Maertens.
Marr KA, Schlamm HT, Herbrecht R, Rottinghaus ST, Bow EJ, Cornely OA, et al. Combination Antifungal Therapy for Invasive Aspergillosis: A Randomized Trial. Ann Intern Med. 2015;162:81-89. doi: 10.7326/M13-2508
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Published: Ann Intern Med. 2015;162(2):81-89.
This article has been corrected. The original version (PDF) is appended to this article as a Supplement.
Invasive aspergillosis (IA) is associated with poor outcomes in patients with hematologic malignancies (HMs) and hematopoietic cell transplantation (HCT). Small studies suggest a role for combination antifungal therapy.
To assess the safety and efficacy of voriconazole and anidulafungin compared with voriconazole monotherapy for treatment of IA.
Randomized, double-blind, placebo-controlled multicenter trial. (ClinicalTrials.gov: NCT00531479)
93 international sites.
454 patients with HM or HCT and suspected or documented IA were randomly assigned to treatment with voriconazole and anidulafungin or placebo. Primary analysis was done in the modified intention-to-treat population of 277 patients in whom IA was confirmed.
The primary outcome was 6-week mortality; secondary outcomes included 12-week mortality, mortality in major subgroups, and safety measures.
Mortality rates at 6 weeks were 19.3% (26 of 135) for combination therapy and 27.5% (39 of 142) for monotherapy (difference, −8.2 percentage points [95% CI, −19.0 to 1.5]; P = 0.087). Secondary mortality outcomes favored combination therapy. Multivariable regression analysis suggested that maximum galactomannan value, Karnofsky score, and baseline platelet count had prognostic significance. Most patients (218 of 277 [78.7%]) had IA diagnosis established by radiographic findings and maximum galactomannan positivity. In a post hoc analysis of this dominant subgroup, 6-week mortality was lower in combination therapy than monotherapy (15.7% [17 of 108] vs. 27.3% [30 of 110]; difference, −11.5 percentage points [CI, −22.7 to −0.4]; P = 0.037). Safety measures, including hepatotoxicity, were not different.
Mortality at 6 weeks was higher than expected, and the difference in mortality was lower than expected, which reduced power to detect a treatment effect. Enrollment was restricted to patients with HM or HCT, which limited generalizability.
Compared with voriconazole monotherapy, combination therapy with anidulafungin led to higher survival in subgroups of patients with IA. Limitations in power preclude definitive conclusions about superiority.
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Hematology/Oncology, Infectious Disease, Pulmonary/Critical Care, Leukemia/Lymphoma.
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